there are several potentially reversible cardiomyopathies that are known to improve when the root etiological factor is addressed.

1. REVERSIBLE
CARDIOMYOPATHY

2. Reversible causes of cardiomyopathy
- Peripartum cardiomyopathy
- arrythymia-mediated cardiomyopathy
- Takotsubo cardiomyopathy
- Alcoholic cardiomyopathy
- Cocaine
- Medications
- End stage renal disease cardiomyopathy
- Cirrhotic
- Endocrine dysfunction
- Nutritional deficiencies
- Electrolyte abnormalities
- Obstructive sleep apnea

3.  Dilated cardiomyopathy (DCM): Characterized by
dilation and impaired contraction of one or both
ventricles
 DCM - caused by a variety of specific diseases
 ≥ 50% of patients with DCM:
- an etiologic basis will not be identified
- Idiopathic DCM

4.  One series- 1278 patients with congestive heart
failure
 Idiopathic — 51 percent
 Idiopathic myocarditis — 9 percent
 Occult coronary disease — 8 percent
 Other identifiable causes — 32 percent
• Felker, et al. The spectrum of dilated cardiomyopathy.
The Johns Hopkins experience with 1,278 patients.
Medicine (Baltimore) 1999; 78:270

5. Clinical presentation
 Most patients present between age : 20-60 years
- Can occur in children and elderly
 Symptoms of CHF
 Incidental detection of asymptomatic cardiomegaly
 Symptoms related to coexisting arrhythmia,
conduction disturbance
 Thromboembolic complications
 Sudden death

6. Reversible Cardiomyopathies
Cardiomyopathies have many etiological factors that
can result in severe structural and functional
dysregulation.
Fortunately, there are several potentially reversible
cardiomyopathies that are known to improve when the
root etiological factor is addressed.

7. Arrhythmia-induced
cardiomyopathy(AIC)
FOUR KEY QUESTIONS
What is AIC?
What is the pathophysiology of AIC?
How do I recognize the patient with AIC ?
How do I manage AIC?

8. Summary of common reversible cardiomyopathies and
proposed mechanisms.

9. AIC is a condition characterized by
either a tachyarrhythmia
(tachycardia - induced cardiomyopathy)
or frequent ventricular ectopy
(PVC - induced cardiomyopathy)
that results in LV dysfunction and heart failure.
The hallmark of this condition is
partial or complete reversibility
once arrhythmia
control is achieved.
What is arrhythmia-induced
cardiomyopathy ?
G. Fenelon, W. Wijns, E. Andries, et al.Tachycardiomyopathy: mechanisms and
clinical implications Pacing Clin Electrophysiol, 19 (1996), pp. 95-106

10.  Fenelon et al proposed the following criteria:
1. Dilatation of the heart or heart failure
1. Chronic or very frequent cardiac arrhythmias, including
incessant SVTs, AF or AFL and incessant VT
• They concluded If chronic tachycardia continued more than
10-15% of the day, with an atrial rate of more than 150% of
that predicted for age, cardiomyopathy occurs
G. Fenelon, W. Wijns, E. Andries, et al.Tachycardiomyopathy: mechanisms
and clinical implicationsPacing Clin Electrophysiol, 19 (1996), pp. 95-106

11. AIC can be classified into 2 categories:
One in which arrhythmia is the sole reason for
ventricular dysfunction
(pure or arrhythmia-induced)
And another in which the arrhythmia exacerbates
ventricular dysfunction and/or worsens HF in a
patient with concomitant heart disease
(impure or arrhythmia-mediated)

12. A 62-year-old man without significant past
medical history presented with new onset
HF symptoms. His ECG on presentation
revealed a wide complex
tachycardia and an echo demonstrated a
LVEF
of 10–15 % with normal LV wall thickness
and a moderately dilated LV cavity.
An EPS was performed, which made the
diagnosis of atrio ventricular
reciprocating tachycardia (AVRT) with a
concealed left lateral accessory pathway,
which was successfully ablated.
A follow-up echo one month later
demonstrated an
improved LVEF to 35–40 % and an echo
performed one year later demonstrated
normal LV wall thickness, cavity size and
systolic function

13. Key features of an arrhythmia that will result in AIC are:
rapid ventricular rates, an irregular rhythm, and asynchronous myocardial
contraction, however not all need to be present to result in AIC

14. Basic causes of arrhythmia-induced
cardiomyopathy.

15. Clinical features
 AGE:
 can occur at any age
 reported in infants, children, adolescents, and adults
 Follows any type of chronic or frequently recurring
paroxysmal tachyarrhythmias
 Presentation:
 Variable
 Palpitations due to tachycardia per se
 Symptoms of heart failure like fatigue, exercise intolerance, dyspnea,
pedal edema etc

16. Primary arrhythmia or primary cardiomyopathy
The chicken-egg dilemma

17. Characteristics of primary cardiomyopathy versus
tachycardia-induced cardiomyopathy

18. AF is the commonest cause of AIC
and is reported to be present in 10-50% of patients with heart
failure

19. PVC-induced cardiomyopathy.
How many PVC's are too much? PVC burden
 The most prominent predictor of cardiomyopathy in patients with frequent
PVCs appears to be the daily burden of PVCs.
 There appears to be a threshold burden of approximately 10,000
PVCs/day for developing AIC.
 Ventricular function can improve if the PVC burden is reduced to
<5,000/day
 Therapy for PVC-mediated AIC should be targeted
at suppressing or eliminating the PVCs and should
include antiarrhythmic therapy and catheter
ablation.
 Catheter ablation has emerged as the definitive
therapy for PVC-mediated AIC, with success rates
ranging from 70% to 90%

20. What is the
pathophysiol
ogy of AIC?

21. Overview of the Current Understanding of AIC,
From Mechanisms to Management and
Prognosis
(J Am Coll Cardiol
2015;66:1714–28)

22. Schematic Illustration of the Natural History and Pathophysiology of Rapid
Pacing–Induced Dilated Cardiomyopathy and Heart Failure
CENTRAL ILLUSTRATION

23. There are no established diagnostic criteria for AIC.
However, in a patient presenting with new onset LV dysfunction and a chronic
or recurrent tachycardia with heart rate over 100 beats per minute, the
diagnosis of AIC may be suggested by the following once ischemic
cardiomyopathy is ruled out:
1.No other cause of non-ischemic cardiomyopathy found
(eg. hypertension, alcohol or drug use, stress etc.)
2.Absence of LVH
3.Relatively normal LV dimensions (LV end-diastolic dimension< 5.5 cm)
4.Recovery of LV function after control of tachycardia (by rate control,
cardioversion or radiofrequency ablation) within one to six months.
5.Rapid decline in LVEF following recurrence of tachycardia in a patient with
recovered LV function after control of tachycardia previously.
cMRI may help differentiate AIC from dilated
cardiomyopathy.
(evidence for LGE, suggesting underlying scar)

24. How do I manage
AIC?
PRINCIPLES OF MANAGEMENT
AIC management should focus on concerted
attempts to eliminate or control the
arrhythmia, with the goal of improving
symptoms, reversing LV dysfunction , and
preventing arrhythmia recurrence

25.  No specific tests or markers available
 A high index of suspicion derived from history and
clinical features remains the only available tool
 Diagnosis should be considered in any patient with
left ventricular systolic dysfunction and chronic or
frequently recurring cardiac arrhythmia

26.  Evidence of previously normal systolic function, is
particularly suggestive of this disorder
 Ventricular rate that causes tachycardia-induced
cardiomyopathy has not been determined, although any
prolonged heart rate greater than 100 beats per minute
may be important.
 Important to recognize that resting heart rates are poor
indicators of overall heart rates in patients with AF
 As heart rate response to exercise may vary
 Patients with well-controlled resting heart rates may
have a rapid ventricular response with minimal activity
and develop tachycardia-induced cardiomyopathy

27.  Assessment of exercise heart rates and 24-hour Holter
monitoring useful in diagnosing tachycardiomyopathy in
patients with AF and ventricular systolic dysfunction
 Imaging : ECHO, C MRI
 ECHOCARDIOCARDIOGRPAHIC INDEX
 Jeong et al-LVEDD ≤ 61mm predicted TIC with a
sensitivity of 100% and specificity of 71.4% in patient
with EF ≤30%
 All patients had improvement of EF≥15% in TIC a finding
not demonstrated in dcmp(change in EF5%)
Jeong YH Diagnostic approach and treatment strategy in tachycardia-induced
cardiomyopathy. Clin Cardiol. 2008 Apr;31(4):172-

28. Atrial flutter
Atrial flutter is more difficult to rate control than AF
Catheter ablation to eliminate atrial flutter is
recommended when AIC is suspected.
For those in whom catheter ablation is not
feasible or desired, cardioversion with
antiarrhythmic therapy or aggressive rate
control should be used.
Supraventricular tachycardias
A curative strategy by catheter ablation should
be pursued whenever possible as first-line
therapy for SVT-mediated AIC.

29. Risk of sudden death
 Long-term survival of patients with
AIC following arrhythmia resolution is
likely; however, concerns remain.
 Sudden cardiac death has been
reported in patients with AIC following
symptom recovery and LVEF
normalization

32. history
 William Mackenzie is credited for having coined the term
‘‘alcoholic heart disease’’ in his treatise Study of the Pulse in
1902.
 references to ill effects from excess alcohol usage abound in
most societies. Examples include the ‘‘Tubingen Wine
Heart’’ described in 1877 and the ‘‘Munich Beer Heart’’ as
reported by German pathologist Otto Bol- linger in 1884

33. Definition and Dose-Time Effects
 Long-term heavy alcohol consumption leading to noni-
schemic dilated cardiomyopathy is referred to as ‘‘alcoholic
cardiomyopathy.’’
 Ever since it became evident that moder ate alcohol
consumption has cardioprotective effects in normal
individuals and those with known heart disease, a matter of
great debate has been the amount and duration of alcohol
abuse required to produce detrimental clinical effects.
 Moderate alcohol consumption (1-2 drinks/day) decreases
cardiovascular and all-cause mortality as well as other
‘‘hard outcomes’’ including coronary heart disease (CHD),
ischemic strokes, and amputations due to PVD

34.  large meta-analysis of 8 studies consisting of 16,000
patients with cardiovascular disease confirmed that light
to moderate alcohol consumption (5-25 g/d) was
significantly associated with a decreased incidence of
cardiovascular and all-cause mortality
Costanzo S, di Castelnuovo A, Donati MB, Iacoviello L, de Gaetano G. Alcohol consumption and
mortality in patients with car- diovascular disease: a meta-analysis. J Am Coll Cardiol 2010;55:
1339e47.
• Although there is a lack of consensus, it appears that
most alcoholic patients with detectable changes in
cardiac structure and function report consuming >90 g/d
of alcohol for ≥ 5 years.
Fauchier L, Babuty D, Poret P, Casset-Senon D, Autret ML,
Cosnay P, Fauchier JP. Comparison of long-term outcome of
alcoholic and idio- pathic dilated cardiomyopathy. Eur Heart J

35.  it is important to note that potential damage to the
heart with longstanding alcohol abuse is not beverage
specific nor quantity specific, but varies based on the
pop- ulation studied and the individual; genetic and
environmen- tal factors and types of beverage
consumed by a culture or person play potential roles.
 The CDC estimates that 61.2% of U.S. adults are
current drinkers, 14% former drinkers, and 5% heavier
drinkers.
 There are 12-14 g or 0.5-0.6 fl oz of alcohol in a
standard drink.
 A 12-oz bottle of beer, a 4-oz glass of wine, and a 1.5-oz
shot of 80-proof spirits all contain the same amount of
alcohol (0.5 oz)

36.  Epidemiology
 Reported incidences of alcoholic cardiomyopathy
have ranged from 21% to 32% of dilated
cardiomyopathies in surveys conducted at referral
centers, but theymight be higher among patient
populations where there is a higher frequency of
alcoholism.
Regan TJ. Alcohol and the cardiovascular system. JAMA
1990;264: 377e81.

37.  Men more commonly develop alcoholic
cardiomyopathy,
 women consistently attain higher maximum blood
alcohol concentrations that men for similar levels of
alcohol consumption. This is likely due to the
greater proportion of body water in men and
larger pro- portion of body fat in women
results in a slower distribution of alcohol from
the blood. Furthermore, women have less amounts of
alcohol-metabolizing enzymes, such as alcohol and
aldehyde dehdrogenases.
 Therefore, women may develop alcoholic
cardiomyopathy earlier and at a lower lifetime dose of
alcohol (40%) compared with men.Urbano-Marquez A, Estruch R, Navarro-Lopez F, Grau JM, Mont L, Rubin E. The effects of
alcoholism on skeletal and cardiac muscle. New Engl J Med 1989;320:409e15.

38. Etiology and Pathophysiology
 difficult to establish a definite causal relationship
between heavy alcohol consumption and heart
failure
 there are data incriminating alcohol in heavy
drinkers with asymptomatic and symptomatic left
ventricular dysfunction (systolic and diastolic).
 Environmental factors (cobalt, arsenic) and genetic
predisposition (HLA-B8, alcohol dehydroge- nase
alleles) have been proposed as triggers or abettors in
the etiopathogenesis of alcoholic heart disease.

39.  Quebec beer-drinkers’’’ cardiomyopathy appeared
as an epidemic among heavy beer drinkers in
Canada in the mid-1960s. was associated with
development of large pericardial effusions and low-
output heart failure
 disappeared when brewers discontinued the prac-
tice of adding cobalt to beer to stabilize the foam.
Cobalt is thought to compete with calcium and
magnesium, leading to inhibition of enzymes
involved in the metabolism of py- ruvate and fatty
acid

40. Genetic factors
 polymorphism of the alcohol dehydrogenase type 3
(ADH3) gene alters the rate of alcohol metabolism.
 It has been shown that moderate drinkers who are
homozygous for the slow-oxidizing ADH3 allele have
higher HDL levels and a decreased risk of myocardial
infarction.
 In contrast, polymorphism of the angiotensin-converting
enzyme (ACE) gene has been implicated in alcoholic
cardiomyopthy. The ACE DD genotype has been noted to
increase the likelihood of development of left ventricular
dysfunction in alcoholics

42. Treatment
 There exist no formal guidelines for the treatment of
pa- tients with alcoholic heart failure. Multiple
studies have shown a tendency toward improvement
in left ventricular ejection fractions in patients who
abstained or drastically decreased their intake of
alcohol.
 55 heavy- drinking men showed improvement in
ejection fractions in those who abstained as well as
those who controlled drinking (<60 g ethanol/day)
Cooper HA, Exner DV, Domanski MJ. Light-to-moderate alcohol
con- sumption and prognosis in patients with left ventricular
systolic dys-
function. J Am Coll Cardiol 2000;35:1753e9.

43.  Medical therapy available for alcoholic
cardiomyopathy is no different from that for other
etiologies of heart failure, except it should include
abstinence from alcohol as a corner- stone
 Survival is poor in those who continue to drink
heavily, with 4-year mortality levels close to 50%

44.  One should follow the heart failure guidelines, such as those
adopted by the European Society of Cardiology or the American
College of Cardiology/American Heart Associa- tion , that
incorporate the use of certain beta-blockers and ACE inhibitors or
angiotensin receptor blockers (ARBs).
 Diuretics and digitalis can be used in the management of
symptomatic alcoholic cardiomyopathy patients.
 Some of these patients may have coexisting nutritional
deficiencies (vitamins, minerals such as selenium or zinc), which
may need correction as well, because they can independently
worsen outcomes or hamper at- tempts at treatment.
 Although few data have been published regarding the benefit of
heart transplantation in patients with end-stage alcoholic
cardiomyopathy, relapse would be a major concern.

45. 45
Cocaine induced cardiomyopathy
• DCM - attributable to the direct toxic effects
• heart failure results from:
- myofibrils destruction
- interstitial fibrosis
- myocardial dilatation
• Unlike other reversible cardiomyopathies cocaine induced CM has typical
echocardiographic features
 High LV mass index
 Increased LV mass
 LV dysfunction
• Treatment similar to other cardiomyopathies but beta blockade should not be
given initially
• B blockers will result in alpha adrenergic receptors being unopposed
therefore –coronary vasoconstriction,LV wall stress and hypertensive crisis
• Benzodiazepine preferred drug

46. 46
Medications
- anthracycline-induced cardiomyopathy - most extensively studied
- cardiomyopathy and clinical heart failure are the main dose limiting
side effects of anthracyclines
- cardiomyopathy can occur within the 1st year and up to a decade
after completion of therapy
risk factors:
1 . cumulative dose of anthracyclines administered
(not to exceed 450 mg/m2 in adults)
2. extremes of age
3. concomitant chemotherapy and radiation
4. history of cardiovascular disease

47. 47

48. 48
Endocrine dysfunction
1. idiopathic hypoparathyroidism
2. excess sympathetic activity in pheochromocytoma
3. Cushing's syndrome
4. .hyperthyroidism or hypothyroidism:
5. Sheehan syndrome
6. Primary adrenal sufficiency

49. END STAGE RENAL DISEASE
CARDIOMYOPATHY
 Associated with LVH nad dilatation
 Progressive LV systolic and diastolic dysfunction
 Cardiomypathy preogresses even after dialysis
 Newer studies have shown improvement in LV
function and even complete resolution of
cardiomyopathy after transplant
Zolty et al Severe left ventricular systolic dysfunction may reverse with
renal transplantation: uremic cardiomyopathy and cardiorenal
syndrome. Am J Transplant. 2008 Nov;8(11):2219-24

50. CIRRHOTIC CARDIOMYOPATHY
 Generally latent and rsesults only after a period of
cardiovascular stress such as exercise,drugs ,infection,
hemoorhage,surgery or TIPS
 There is systolic and diastolic dysfunction
 Severity is direclty related to the severity of liver disease
 Mechanism:reduced beta adrenoreceptors signal
transduction,defecetive excitation contraction
coupling,increased activity of cardiodepressant substances
such as cytokines,endogenous cannabinoids and nitrous oxide
 Liver transplantation:regression of LVH,improvement in
diastolic and normalisation of systolic function
 Patients with hepatitis c, amyloidosis or hemochromatosis
less likely improvement in cardiac functiom

51.  HYPERTHROIDISM
 upregulate α-chains, but downregulate β-
chains in myocytes, which ultimately leads to
faster myocardial fibril shortening.
 Thyroid hormones have also been shown to
affect the ion channels, including Na+/K+
ATPase, Na+/Ca+2 exchanger, and various
K+ channels by inducing positive inotropic
effects, thereby prolonging activation of Na+
channels and shortening action potential
durations
 hormones have vasodilatory effect on
peripheral arteries.
 The combined effort of these mechanisms can
lead to systemic changes in cardiac function
due to reduced PVR, activation of the renin–
angiotensin mechanism, LVEDV and
increased preload.
 The increased preload and decreased
peripheral vascular resistance leads to a high
cardiac output, even at rest, resulting in CM.
 HYPOTHYROIDISM
 Causes a low cardiac output CM via the same
pathways mentioned above, however, by
downregulating the previously mentioned
receptors/channels causing decreased
myocardial excitation and contractility
leading to a low-output CM.

52. Management of CM induced by dysthyroidism
(hyper- or hypothyroidism)
 similar algorithm to typical CHF regi- men.
 addressing the root etiol- ogy, whether it be excess or deficiency of thyroid
hormones.
 There is, however, promising data showing that the use of β-adrenergic
blockade may be beneficial in these patients.
 In a small study by Biondi et al, hyperthyroid patients treated with the selective
β
1
-adrenoceptor antagonist bisoprolol experienced normalization of the LV
mass index and LV systolic function after 6 months of treatment.
 Similar results were established in a case study published a year later in which
the use of β-adrenoceptor blockers showed clinical improvement in a patient
with dilated CM caused by hyperthyroidism.
 It is also worth mentioning the association between hyperthyroidism and AF.
One study estimated the prevalence of AF in thyrotoxicosis to be 13%.
 This is very important as uncontrolled AF is associated with a tachycardia-
induced CM

53. 53
Selenium deficiency and cardiomyopathy
Selenium deficiency:
- identified as a factor causing HF syndromes in areas of very
low selenium intakes( China )
- endemic selenium-responsive cardiomyopathy Keshan disease
Similar cases :
- HIV-infected patients
- subjects on parenteral nutrition
- Crohn’s disease
Possible causes of Keshan disease are:
- viral infection
- nutritional factors
(insufficient Zn or molybdenum, excessive barium or lead)
Selenium deficiency :
- decreases the activity of glutathione peroxide
- resulting in increased free radicals > toxic to cardiac myocytes

54. 54
Thiamine:
- plays an important role in normal oxidative phosphorylation and
myocardial energy production
- deficiency initially presents as a high output state secondary to
vasodilation
- followed by eventual depression of myocardial function –
- development of a low output state

55. 55
Electrolyte abnormalities:
Chronic hypophosphatemia and hypocalcaemia:
- reversible cardiomyopathy
- Bacterial, spirochetal, rickettsial, fungal, protozoal, helminthic
infections
- implicated as causes of necrotic or inflammatory lesions
- may lead to dilated cardiomyopathy
Infections :

57. TAKOTSUBO CARDIOMYOPATHY
“Transient left ventricular dysfunction triggered by
stress, with left ventricular regional wall motion
abnormalities extending beyond a single epicardial
coronary artery distribution and without any
coronary lesion. “
Mansecal N, El Mahmoud R, Dubourg O. Occurrence of Tako-Tsubo
Cardiomyopathy and Chronobiological Variation. J. Am. Coll.Cardiol.
2010;55;500-501

58. Japanese octopus fishing pot :
Takotsubo
It is so named due to the appearance
of the left ventriculogram is systole

60. History
• The term ‘‘stress cardiomyopathy’’ was firstly used in 1980 by Ceblin
and Hirch, who described sudden death in 11 patients without any
evidence of CAD in autopsy results.
• Iga et al
reported a case of reversible left ventricular
dysfunction associated with pheochromocytoma
takotsubo appearance was first described,
although they did not use the term
takotsubo.
Jpn Circ J. 1989;53:813– 818
• Sato et al
first described this reversible
cardiomyopathy as tako-tsubo-like left
ventricular dysfunction
Clinical Aspect of Myocardial Injury: From Ischemia to Heart Failure. Tokyo,
Japan:
Kagakuhyouronsha; 1990:56–64.
• Outside Japan, this phenomenon was called apical ballooning or
stress cardiomyopathy

61. Epidemiology
• Until 2000, a few case reports were published, but the
presentation of Takotsubo cardiomyopathy has increased
gradually since 2001.
• The true prevalence of the apical ballooning syndrome
remains uncertain.
• probably accounts for 1% to 2% of all cases of suspected acute
coronary syndromes
.
Chest. 2007;132:809–
816
• Bybee et al. reported that the apical ballooning syndrome
accounted for 2.2% of the ST-segment elevation ACS presenting
J Nucl Med 2004;45:1121–1127
• Matsuoka et al.: 2.2% of suspected
ACS
Am J Cardiol 2003;92:230–233
• Akashi et al.: 2.0% of patients with sudden onset of heart failure
and abnormal Q waves of ST-T changes (suggestive of acute MI
onadmission
)
Am J Cardiol 2004;94:343–346

62. Women>Men
• Females are affected more than men
• 90% of cases involve women
• Majority are post-menopausal
• Mean age 68yrs
• Sharkey et al. prospectively assessed 136 consecutive TC patients and
confirmed that TC predominantly appears in postmenopausal (mean
age, 68 ` 13 years) women (96%) while the occurrence in younger
group is relatively rare (10% in <50 years group)
Sharkey SW, Windenburg DC, Lesser JR, Maron MS, Hauser RG,
Lesser JN, et al. Natural history and expansive clinical profile of
stress (Takotsubo) cardiomyopathy. J Am Coll Cardiol
2010;55:333–41.

63. Shimizu M, Kato Y, Masai H, Shima T, Miwa Y. Recurrent
episodes of Takotsubo-like transient left ventricular ballooning
occurring in different regions: a case report. J Cardiol

64.  According to Ramaraj R et al frequwncy of classical,reverse and mid
cavity types of TTC were found to be 67%,23% and 10% respectively
 recent studies reported TC with right ventricular involvement that
should be classified separately due to the extreme clinical
manifestation
 RV RWMA were reported in 26% of TC patients, when the most
affected RV segments were the apico-lateral (89%), the antero-lateral
(67%) and the inferior segment (67%)
tHaghi D, Athanasiadis A, Papavassiliu T, Suselbeck T, Fluechter S, Mahrholdt H, et al. Right ventricular
involvement in Takotsubo cardiomyopathy. Eur Heart J 2006;27:2433–9.

65. Possible mechanisms
• Multivessel Epicardial Coronary Artery Spasm
• Coronary Microvascular Impairment
• Catecholamine Cardiotoxicity (major
contribution)
• Neurogenic Stunned Myocardium
• Focal myocarditis
• Structural changes and oxidative stress theory

66. Multivessel Epicardial Coronary Artery Spasm
• Activation of sympathetic and adrenomedullary hormonal
systems due to emotional or physical stress resulting in
adrenergic storm.it is however unclear how these
alterations result in myocardial stunning
• One possible mechanism is increased sympathetic tone
from mental stress causing epicardial coronary artery
spasm in patients without CAD

67. Coronary Microvascular Impairment
 Sympathetically medicated microcirculatory
dysfunction causing abnormal coronary flow in
absence of obstructive disease
• Kume et al, Yoshida et al
: reported impaired coronary perfusion and severe
myocardial metabolic abnormalities
– basis of results of thallium-201 myocardial single-photon emission
computed tomography and 18F-fluorodeoxyglucose myocardial
positron

68. Catecholamine Cardiotoxicity
(major contribution)
• Plasma levels of both epinephrine and norepinephrine were remarkably increased in the
stress cardiopathy patients than acute MI
• Wittstein et al.
: elevated catecholamine levels are not uniformly found in patients with these syndrome
N Engl J Med. 2005;352:539 –
548
• Myocardial histological changes :
strikingly resemble those seen in catecholamine cardiotoxicityin both animals and humans.
Int J Cardiol. 1994;45:23–33,; Chest. 1991; 99:382–385
differ from in ischemic cardiac necrosis include contraction band necrosis, neutrophil
infiltration, and fibrosis.
These findings probably reflect consequences of high intracellular concentrations of Ca2􏰃,
and it has been proposed that Ca2􏰃 overload in myocardial cells produces the ventricular
dysfunction in catecholamine cardiotoxicity.
Although diffuse heart failure can produce high circulating catecholamine concentrations, the
attained levels are not nearly as high as in takotsubo cardiomyopathy and by definition would
not explain the takotsubo pattern.

69. Catecholamine Cardiotoxicity
(major contribution)
• Circulating epinephrine exerts far more potent hormonal effects on the heart than
norepinephrine
 epinephrine-induced toxicity
• Emotional stress:
Concurrent cardiac neuronal and adrenomedullary hormonal stimulation

70. Nat Clin Pract Cardiovasc Med. 2008;5:22–
29
it is observed the importance of apical -basal gradients of b-adrenergic receptors
and sympathetic innervation in mammalian lv, where apex contains the highest b-
adrenergic receptors and the lowest sympathetic nerve density. the presence of
ventricular b-adrenergic receptors gradient results in increased apical
responsiveness to catecholamines predomi- nantly epinephrine [ secondly,
epinephrine, at high levels can have negative inotropic impact and trigger a switch
from intracellular trafficking, from g
s
(stimulatory) protein to g
i
(inhibitory)
protein signaling through the b
2ar
. this negative inotropic affect is greatest in
apex where the density of b-adrenergic receptors is highest [

71.  the reason for the distribution of myocardial dysfunction
in TTC is not well understood.
 The distribution ,density and sensitivity of adrenergic
receptors may determine area of hypokinesis
 Adrenoreceptor density is highest in apex
compared with the base in postmenopausal
women apical variant in older women
 Ramraj et al hypothesized that the presentation
of inverted TTC at a a younger age may be due to
abundance of adrenoreptors at the base
comapred to apex at younger age

72. Focal myocarditis
• not well supported by the data
• Viral titers do not rise after the initial event
• Biopsy findings are not suggestive of
myocarditis

74. Structural changes and oxidative stress theory
• Transient structural alteration, including disorganization of the contractile and cytoskeletal
proteins with an increase of the extracellular matrix, has been demonstrated in the
myocardium
• Important factor in the development of takotsubo CMP is the presence of abnormal myocardial
functional architecture such as localized midventricular septal thickening.
• Wittstein et al. reported supraphysiological levels of plasma catecholamines and stress-related
neuropeptides as potential sources of reactive oxygen species (ROS)
• ROS production is activated and results in an upregulation of the antioxidant defense. ROS when
stimulated by catecholamines or ischemia, have the potential to injure vascular cells and cardiac
myocytes directly.
• initiate a series of local chemical reactions and genetic alterations amplification of the initial ROS-
mediated cardiomyocyte dysfunction and cytotoxicity
• Exposure of normal myocardium to ROS generating systems alters myocardial function through
persistent cellular loss of K+, depletion of high-energy phosphates, elevated intracellular calcium
concentration, loss of systolic force development, a progressive diastolic tension and depressed
metabolic function
• In Biopsies : different functional gene sets such as Nrf2-induced genes, were triggered by oxidative
stress

75. Presentation
Cannot distinguish between Takotsubo and
STEMI at presentation!!!

76.  There are no worldwide valid criteria for the TC diagnosis
yet. In 2004, the diagnostic criteria of TC by the Mayo
Clinic, which have been modified in 2008 and are widely
used for the diagnosis of TC were proposed
All four must be present
Akahashi Y, Nef H, Möllman H, Ueyama T. Stress Cardiomyopathy. Annu. Rev. Med. 2010. 61:271-286

77. 67 72
91 95
Clinical manifestation
69.8 Tsuchi
h ashi
et al
Kurow
s ki
et al
Kuris
u et
al
Sharke
y et al
Wittst
ei n
et al
Inoue
et al
Sat
o
et
al
Bybe
e et
al
Yoshid
a et al
Akas
hi et
al
Subject, n
88 35 30 22 19 18 16 16 15 13
Country
Japan
Germa
n
y
Japan US US Japan Japan US Japan Japan
Age, y Average
69.8
70 65 61 76 71 71 72 73
Women, %
86 94 93
Average 91.2 94 94 100 80 85
Precedin
g
emotiona
l
stressor,
%
20 42 17 86 100 11 38 40 31
Precedin
g
physical
stressor,
%
43 42 17 14 39 100 44 40 69
Sum of
stressor,
%
63 84 34 100 100 50 100 82 80 100

78. Tsuchi
h
ashi
et al
Kurow
s ki
et al
Kuris
u
et al
Sharke
y et
al
Wittst
ei n
et al
Inoue
et
al
Sat
o
et
al
Bybe
e
et al
Yoshid
a et
al
Akas
hi
et al
Chest
pain,
%
67 67 91 95 72 100 69 87 54
ST
elevation,% 90 69 100 59 11 100 56 81 87 92
ST
elevation
in
precordial
leads, %
85 97 59 100 81 92
Q waves, % 27 45 37 56 31 7
Mean
QTc,
ms
542 501 508
Elevation in
cardiac
enzyme, %
56 56 100 85
Initial EF, % 41 50 49 29 20 49 40 43 42
F/u EF, % 64 68 69 63 60 66 60 76 65
Clinical manifestation

79. 0
1
/16(6
)
0
This table is adapted and modified from Circulation. 2008;118:2754-
2762
Clinical manifestation
Tsuchihas
hi et al
Kurows
ki et al
Kuris
u et
al
Sharke
y et al
Wittstei
n et al
Inou
e et
al
Sat
o
et
al
Bybe
e et
al
Yoshid
a et
al
Akas
hi et
al
Time of
recovery,
d
Average 15.7
11.3
24 21 17.7 8 11 17
Pul. Edema, % 22 3 0 16 28 6 44 0
IABP, % 8 0 18 16 6 0 6 7 15
Coronary
stenosis
>50%
0 0 0 0 5 0 0 0 0
Spont.
Multivess
el
0 0 10 0 0 0 0 0 0
spasm, %
Provocable
multivessel
spasm,
n/n(%)
Transient
intraventricul
ar pressure
gredient, %
In-hospital
5/48(10)
18
6/14(43)
23
Les
s
than
0/6(
0)
10
%
13
1/6(17)
14
0/11(0)
mortality, % 1 3(9) 0 00 6 0 0 0 8
Documented
recurrence, 2/72(3) 2(6) 0 2
/
Les
s
than 10%

80. symptoms
 Commonly the clinical presentation is
o angina-like chest pain at rest (68%)
o and dyspnea (17%)
o while syncope and
o out-of-hospital cardiac arrest is rare
o Hemodynamic compromise is rare, but mild to moderate congestive heart
failure is reported frequently.
o Despite hypotension, that is common in TC patients, due to the dynamic LV
outflow tract obstruction and reduction of stroke volume, cardiogenic shock
is reported as a rare complication (1.5%)
Tsuchihashi K, Ueshima K , Uchida T, et al. 2001 Transient left ventricular apical ballooning
without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial
infarction. Angina Pectoris –Myocardial Infarction Investigations in Japan. J. Am. Coll.
Cardiol. 38: 11-18

81. History
 Acute emotional stress
(25% of cases)
 Physical stressor
(30% of cases)
 Idiopathic
(30% of cases)
Unexpected death in the family
Confrontational argument
Severe anxiety
Asthma attack
Exhaustion
Sepsis

82. 82

83. ecg
• the classical abnormality on ECG is ST segment elevation
mimicking acute STEMI in about 70–80% of cases accompanied by
T wave abnormalities (64%) transient pathological Q wave (32%)
reduction of the R wave amplitude or absence R wave in anterior
chest leads, new bundle-branch block and QTc interval
prolongation
• The ECG cannot reliably diagnose TC, but it is reported that the
magnitude of ST shift is usually less pronounced in comparison to
STEMI
• Also, the recent studies described a new and simple ECG criterion
to differentiate TC from acute anterior STEMI. It was reported that
ST elevation ≥1 mm in at least one of the leads V3–V5 without ST
elevation in lead V1 identified TC with a sensitivity of 74.2% and a
specificity of 80.6%
Gianni M, Dentali F, Grandi AM, Sumner G, Hiralal R, Lonn E.
Apical ballooning syndrome or Takotsubo cardiomyopathy: a
systematic review. Eur Heart J 2006;27:1523–9.
Tamura A, Watanabe T, Ishihara M, Ando S, Naono S, Zaizen H,
et al. A new electrocardiographic criterion to differentiate
between Takotsubo cardiomyopathy and anterior wall ST-
segment elevation acute myocardial infarction. Am J Cardiol
2011;108:630–3.

85. ECG
 At presentation:
ST-elevation in pre-cordial leads

86. Repeat ECG
 Later that day
Resolution of ST-elevation
Development of T-wave inversion

87. Biochemical changes
 Plasma catecholamines are higher in TTC than observed in killip class 3 mi
 Consistent with the ECG findings, TTC is associated with elevation in cardiac
biomarkers of myonecrosis.
 The initial description by Tsuchihashi reported creatinine kinase elevation in
56% of the patients. Subsequent studies using cardiac troponin report almost
universal elevations, because of the greater sensitivity of the biomarker, especially
with contemporary assays.
 The pattern of troponin elevation differs considerably from acute
STEMI. Peak troponin T levels are modest, mean ~60-fold the upper
limit of normal (ULN, defined as 99 th per- centile) as opposed to >400-
fold the ULN for acute STEMI, similar to those seen in non-ST-
segment elevation MI.
 Troponins are higher in inverted variant as larger ventricular mass involved
 Nascimento et al used this finding of modest elevation of troponin in patients with
TTC to devise a criterion for differentiating between STEMI and TTC. They derived
the troponin- ejection fraction product (TEFP) by obtaining the product
of the peak troponin I level and the echocardiographically obtained
ejection fraction. A TEFP ≥ 250 had a sensitivity of 95 %, specificity of
87% and overall accuracy of 91% to identify STEMI.
 Plasma B-type natriuretic peptide (BNP) levels are usually higher in TTC than in
STEMI, they are more eleveated in apical and midventricular pattern reflective of
more severe symotoms a nd higher NYHA class

88. Coronary angiography and noninvasive cardiac
imaging
 absence of obstructive CAD or acute plaque rupture on coronary
angiography while the coronary artery disease may coexist by the
prevalence in the population at risk
 Typical TC is described as the akinesia/hypokinesia of the apical
midventricular segments and hyperkinesia of the basal segments. For this
typical contraction pattern TC is also known as apical ballooning syndrome
• As the important criteria is the expansion of RWMA that typically
extends beyond of the distribution of any single coronary artery
• TTE is helpful in initial investigation to evaluate RWMA and LV
dysfunction . The evaluation of the true anatomic apex can be demanding
due to the bad condition of the acutely ill patient. The initial diagnosis of TC
in most cases is made in catheterization laboratory where the coronary
angiography and ven- triculography is performed in order to exclude acute
coronary syndrome
• Nevertheless, the precise evaluation of systolic LV function and possible LV
outflow tract obstruction is necessary.
Zeb M, Sambu N, Scott P, Curzen N. Takotsubo cardiomyopathy: a diagnostic challenge. Postgrad
Med J 2011;87:51–9.

90.  According to the recent studies the mean of LV ejection fraction (LVEF) is
ranging from 20% to 49% at the initial presentation of TC and over a period
of days to weeks the dramatic improvement of the LV function (the mean
LVEF 60–76%) is observed for the majority of patients
 However, echocardiography is not a sufficient tool to make a proper
differential diagnosis of TC.
 Cardiac magnetic resonance imaging (MRI) becomes widely acceptable to
differentiate TC from other troponin positive chest pain associated causes
when obstructive CAD is absent
 Characteristic sign of TC in cardiac MRI is the absence of late
gadolinium contrast enhancement It is known that gadolinium
release into interstitial space of damaged myocardium and is
very sensitive in conditions with severe LV dysfunction such as
STEMI or myocarditis. There is a lack of data to explain why
such extended LV impairment with positive troponin is not
causing the late enhancement in cardiac MRI, hence it supports
the hypothesis of myocardial stunning

91. management
• Treatment of TCM during the acute phase is mainly symptomatic
treatment.
• Intra-aortic balloon pump equipment is required for hemodynamically
unstable patients in addition to cardiopulmonary circulatory support and
continuous veno-venous hemofiltration
• There is controversy on the use of cardiac stimulants because of increased
circulating catecholamines.
• However, cardiac stimulants are used in 20%-40% of patients with Usage
of anticoagulants may be considered at least until systolic function is
recovered.

92.  b-Blockers are also recommended when the LV outflow track
obstruction due to the hyperdynamic basal contraction is present .
 Congestive heart failure is reported as the most common complication
of TC. It occurs in approximately 20% of patients especially when the
RV dysfunction is involved . Diuretics are well established to treat
congestive heart failure and might be useful in these patients
 As the studies suggest, hypotension may be often present in the acute
phase of TC as a primary hypotension due to the LV dysfunction or a
secondary one, when LVOT obstruction and systolic anterior motion of
the mitral valve is occurs.
 In order to administer the appropriate treatment the underlying cause
should be immediately found.
 It is recommended to treat LV dysfunction with the insertion of IABP
rather than inotropes that may worsen the condition by adding to the
existing excess of catecholamines and/or increasing LVOT obstruc- tion
For the reducing of the dynamic LVOT obstruction, basal
hypercontractility and increasing of LV cavity size, intravenous fluid
with short acting b-blockers should be cautiously administered


93.  severe LV outflow tract obstruction with hemodynamic compromise,
treatment with a β-blocker or α-adrenoceptor agonist such as
phenylephrine and volume expansion should be considered.
 Calcium channel blockers can be used to decrease LV outflow tract pressure
gradient. It is of utmost importance to avoid treatment with nitrates or inotropic
drugs in these cases
 For patients with suspected vasospasm, the use of calcium channel
blockers such as verapamil or diltiazem is suggested
 Hemodynamically stable patients are often treated with diuretics, angiotensin-
converting enzyme (ACE) inhibitors and β-blockers.
 To reduce the risk of thromboembolism, patients with loss of motion of the LV apex
should be treated with anticoagulant therapy until the contractility of the apex is
improved unless there is a definite contraindication.
 There is no consensus regarding long-term management of TCM, although
it is reasonable to treat patients with β-blockers and ACE inhibitors during
the ventricular recovery period. However, no data support the continuous use
of these drugs for the prevention of TCM recurrence or improvement of survival
rate. After LV function normalizes, physicians may consider
discontinuation of these drugs

94. Prognosis
 TC is rapidly reversible acute heart failure as reported previously,
however in-hospital mortality rate of TC is 1.2–4.2%
 Brinjikji et al. identified 24,701 patients of TC and documented that
male patients had higher mortality rate comparing to female
patients (8.4% vs. 3.6%, P < 0.0001) .
 The higher mortality rate in male patients was explained by higher
incidence of underlying critical illness in male patients (36.6% vs.
26.8%, P < 0.0001), average mortality rate among these patients
 The most commonly reported complications of TC (reported in 19–
34.5% of TC cases) are severe heart failure, intra-aortic balloon
pump (IABP) placement, ventricular fibrillation/cardiac arrest,
pulmo- nary edema, and cardiogenic shock, while other
complications including cerebrovascular accidents, thrombus,
pneumothorax and ventricular septal defects are rare